The central hypothesis of this research program is that readily accessible body fluids and/or physiological functions provide biomarkers which may be predictive of: a) exposure, b) adverse effects, and/or c) unusual susceptibility, to toxic substances in the environment. This Program Project includes 11 integrated projects focused around this central theme: Project 1 will continue investigations on glutathione and glutathione biosynthesis as an integrative biomarker for oxidative damage induced by a variety of chemicals found at hazardous waste sites. Project 2 will examine whether urinary porphyrin concentrations vary in response to the biological actions of trace metals in target tissue cells, and therefore can serve as a quantitative biomarker of metal exposure and effects. Project 3 continues to investigate whether parameters of neurotransmission present in blood cells might represent good biomarkers for the same parameters in the central and peripheral nervous system, with a specific focus on muscurinic cholinergic receptors. Project 4 will utilize established cultures of human hepatoma cells and freshly isolated human blood lymphocytes and pulmonary macrophages to study the effects of PCBs, PAHs, benzene and other chemicals on cytochrome P-450 expression to determine if the "fingerprint" of P450 gene products can be used as a biomarker of exposure. Project 5 will continue work on the development of biological treatment systems for removing chlorinated organic contaminants in groundwater and leaches, using mixed microbial cultures in a biological reactor. Project 6 will examine wildlife as biomarkers of exposure to toxic chemicals at hazardous waste sites, using starlings and deer mice inhabiting such sites. Project 7 will examine the presence of oxidative DNA damage as a biomarker of adverse ecological impact in fish exposed to highly contaminated sediments at a Superfund site in Puget Sound. Project 8 will evaluate human sperm structure and function as a biomarker of adverse reproductive effects in males exposed occupationally to lead. Project 9 will continue to evaluate physiologically-based pharmacokinetic modelling to inter-individual differences in absorption, metabolism and excretion of alkylbenzenes in humans following controlled inhalation exposures. Project 10 is a new case-control ecogenetic epidemiology study to assess the hypothesis that oxidative stress from environmental pollutants, particularly metals and pesticides, is a significant risk factor for Parkinson's disease, and will utilize biomarkers of oxidant stress developed in other projects to determine potential genetic susceptibility as a modifier of risk. Project 11 is an epidemiology study of workers occupationally exposed to perchlorethylene, and will examine for the first time the prospective relationship between chronic exposure to PCE and symptoms, neurobehavior, neurophysiologic and neurochemical biomarkers of CNS dysfunction. Administrative, Analytical and Training Cores are proposed to foster the productivity and integration of these studies.